The prevalence of allergic asthma and allergic diseases has reached epidemic proportions in both adult and pediatric, developed and developing populations (Eder et al., 2006, N. Engl. J. Med., 355:2226-2235). The lack of early childhood infections or microbial exposure due to improved sanitation, and the gradual loss of the indigenous microbiota, have alternately been proposed to account for this major public health trend (Blaser, 2009, Nat. Rev. Microbiol., 7:887-894). In 2011, 235-300 million people globally have been diagnosed with asthma, and it caused 250,000 deaths.
Asthma is now the most prevalent chronic disease in childhood in developed countries; approximately 300 million people suffer from this disease worldwide. Asthma is caused by a combination of genetic and environmental factors. The Global Initiative of Asthma defines asthma as a chronic inflammatory disorder of the airways. Chronic pulmonary inflammation is associated with airway hyper-responsiveness, which leads to the classical symptoms of asthma: recurrent episodes of wheezing, breathlessness, chest tightness and coughing. The most common clinical phenotype is allergic asthma. In childhood, more than 90% of patients with severe asthma are allergic; among asthmatic adults, 60% are sensitized to common aero-allergens (Holgate et al., 2003, Eur. Respir. J., 22:470-477). In allergic asthma, inflammation and airway obstruction are triggered by allergen exposure in atopic individuals. The pathophysiology underlying the disease is rather complex. The inflammatory processes underlying the development of allergic airway disease have been investigated in humans and also in animal models of the disease. The understanding of the different cell types and mediators involved in asthma development has increased in the last decade. Indeed, findings support an important role of Th2 cells and Th2 cytokines (IL-4, IL-5 and IL-13) in the development of allergen-induced inflammation and airway hyper-responsiveness (AHR).
The state-of-the-art immunomodulatory treatment of acute symptoms of asthma involves inhaled or oral corticosteroids. Asthma patients generally respond to 132-adrenergic receptor agonists (such as salbutamol) and leukotrienes, which relax smooth muscle cells. In very severe cases, intravenous administration of corticosteroids or immunomodulatory drugs such as neutralizing antibodies to interleukins and hospitalization may be required. Anti-IL-13, anti-IL-5 and anti-IL-9 monoclonal antibodies are all currently in clinical trials for asthma.
Helicobacter pylori is a persistent bacterial pathogen colonizing the gastric mucosa of humans. It is typically acquired in early childhood and, in the absence of antibiotic therapy, may persist for the entire lifespan of the host. The extraordinary ability of H. pylori to resist a vigorous adaptive immune response driven in large part by Th1 and/or Th17-polarized effector T-cells has been attributed to its adaptation to and manipulation of the human innate and adaptive immune systems. H. pylori has colonized its human host for at least 60,000 years and during this long period of co-evolution has evolved elaborate ways to systemically manipulate adaptive immune responses and to promote its persistence through the preferential induction of regulatory T-cell (Treg) over immunogenic T-cell responses through T-effector cell responses. Treg-predominant responses are characteristic of heavily colonized but asymptomatic carriers.
It has been shown that experimental live H. pylori infection, especially when initiated during the neonatal period, protects effectively against allergen-induced asthma that is induced by allergen sensitization and challenge (Arnold et al., 2011, The Journal of Clinical Investigation, 121:3088-3093). Mechanistically, asthma protection is due to the development of (Treg-mediated) immune tolerance to H. pylori, which cross-protects against allergen-specific Th2 responses. The protective effects of live H. pylori are abrogated by antibiotic eradication therapy clearing the bacteria (Arnold et al., 2011, supra). Similarly, the induction of protective Tregs required live bacteria in vivo and could not be achieved by dead extract.
Aside from Tregs, dendritic cells (DCs) have emerged as a critical cell type required for immune tolerance. H. pylori-experienced DCs are reprogrammed toward a tolerance-promoting phenotype in vitro and in vivo (Oertli et al., 2013, PNAS, 110(8):3047-3052). It has been observed that DC reprogramming requires two H. pylori-secreted proteins (virulence determinants or factors), the vacuolating cytotoxin (VacA) and the γ-glutamyl-transpeptidase (GGT) (Oertli et al., 2013, supra), since H. pylori mutants that lack one of the two virulence factors (but are otherwise wild-type) fail to reprogram DCs in vivo and in vitro, and therefore cannot induce Tregs with suppressive activity in mice (Oertli et al., 2013, supra). As a consequence, both H. pylori mutant strains are cleared effectively by the mice (Oertli et al., 2013, supra). Furthermore, both GGT and VacA have been used or reported to be used to trigger vaccine-induced protective immunity to H. pylori, i.e., with the opposite goal (strong T effector rather than Treg responses) of the present aim of the invention (Malfertheiner et al., 2008, Gastroenterology, 135(3):787-95).
The use of live H. pylori as a therapeutic intervention or preventive measure has been unattractive due to the well-documented carcinogenic potential of chronic infection with this organism, since H. pylori induces gastric and duodenal ulcers (Marshall et al., 1984, Lancet, 1:1311-1315), and is also widely accepted to be the leading cause of gastric adenocarcinoma (Parsonnet et al., 1991, N. Engl. J. Med., 325:1127-1131). Further, it is important to note that those vaccination strategies using H. pylori are aimed at inducing an immune response that would protect the subject from H. pylori infection and counter-acting the ability of H. pylori to avoid or bypass the immune system response.
Since all the current treatments of asthma induce more or less severe side effects, alternative treatment strategies are desperately needed. Therefore, there are important needs for new strategies of prevention of asthma development, particularly for children and young people that present a predisposition towards developing hypersensitivity reactions and for treatment of asthma causes and symptoms.